Recombinant interferon (IFN) gamma has previously been shown to activate monocytes in patients with malignant melanoma rendered disease-free with surgery. The purpose of this protocol was to test three different doses of recombinant IFN-gamma in patients with metastatic disease (high tumor burdens) to see is there was an optimal immunomodulatory dose in these patients. We enrolled 18 patients on this study and treated 5 patients at each of the following three dose levels: 0.01 mg/m sq, 0.1 mg/m sq, and 0.25 mg/m sq. In general, therapy was well-tolerated and toxicities were mild. Serial blood sampling for evidence of monocyte activation showed that the two higher doses produced consistent increases in monocyte activation. Statistical analysis revealed no significant differences between these two doses and there was no evidence for any superiority of the 0.1 mg/m sq dose over the 0.25 mg/m sq dose. This study demonstrates that patients with relatively high tumor burdens (patients with metastatic malignant melanoma) can have significant monocyte activation induced by IFN-gamma. In contrast to our previous study, in patients with relatively low tumor burdens, this current study did not show any superiority of the 0.1 mg/m sq dose over the 0.25 mg/m sq dose. Because the 0.25 mg/m sq dose of IFN-gamma has been studied in a phase II study in patients with metastatic malignant melanoma and found to have a low response rate, we did not further pursue investigation of the effectiveness of 0.1 mg/m sq of IFN-gamma in patients with metastatic melanoma.